A surprising result poses new questions about the role of an "essential" brain protein.

A lack of dynamin 1 (green) causes synaptic vesicles (blue) and endocytic buds to arrest at the pre-fission stage, as revealed here by electron tomography.

Imagine your mechanic yanked the engine out of your car. You buckle up, turn the ignition, and off you drive, undoubtedly with a shattered notion of how automobiles work. That's essentially what researchers led by HHMI investigator Pietro De Camilli experienced earlier this year when they eliminated a brain protein from mice thought to be an engine for transmitting nerve impulses.

The Yale University School of Medicine team and their colleagues knocked out the dynamin 1 gene, which encodes a protein implicated in pinching off budding synaptic vesicles from the plasma membrane of neurons—a process that recycles these vesicles once they have released their neurotransmitter content. Work in fruit flies and other species had led neurobiologists to presume dynamin 1 played an essential role.

But nobody had performed the definitive test—removing dynamin 1 from mice—to see what happened. "We thought it would be a no-brainer—no dynamin 1, no synaptic vesicles," says De Camilli. Astoundingly, when his team created dynamin 1 knockout mice, the newborns appeared normal and lived for up to two weeks, as reported in the April 27, 2007, issue of Science.

Microscopic examination revealed that the neurons of the knockout mice contained plenty of synaptic vesicles, though they tended to be larger and less uniform in size, and numerous budding vesicles stayed attached to the plasma membrane in grape-like clusters. Electrophysiology and other biophysical tests showed that the neurons behaved almost perfectly under normal stimulation, failing only under strong electrical stimulation.

Because mammals have two additional dynamin genes, producing slightly different forms of the protein, De Camilli suspects that one or both of these variants may compensate for dynamin 1 in the knockout mice. But given that these variants together represent less than 10 percent of the total dynamin in the brain, he wonders whether dynamin in any form is truly essential for synaptic transmission. The De Camilli lab plans to delete the other two forms to find out.

Scientific Image: Mitsuko Hayashi, Shawn Ferguson, and Pietro De Camilli